The overall goal of this research proposal is to understand the short- term modulation of synaptic transmission by neurotrophins. There is increasing evidence that neurotrophin expression and neuronal excitability are intimately related. Neurotrophins are thus emerging, beyond traditional "growth and survival factors", as potential mediators of synaptic plasticity. Given the fundamental importance of rapid synaptic changes in nervous system functioning, a role for neurotrophins in the rapid mediation of synaptic plasticity is compelling. Furthermore, the likely involvement of these growth factors in such diseases as Alzheimer's and Parkinson's underscores the importance of understanding neurotrophin effects in the nervous system. Three questions will be investigated to understand the specific, short-term effects of neurotrophins on synaptic transmission: 1) How is synaptic transmission in neurons modulated by each member of the neurotrophin family? 2) At what locus, presynaptic or postsynaptic, do neurotrophins act to modulate synaptic transmission? 3) What are the specific molecular mechanisms by which neurotrophins modulate transmission? The proposed experiments will be addressed in CA1 hippocampal pyramidal neurons, which express the neurotrophins and their receptors in abundance, and are well-studied as a model of neuronal plasticity. Whole-cell patch clamp methods will be used to characterize synaptic currents in dissociated, "autaptic" neurons -- isolated neurons which have formed synapses on themselves. The use of such a simplified, yet functionally relevant model of a synapse will enable the understanding of specific neurotrophin effects on synaptic transmission, and help to elucidate the general role of neurotrophins in neuronal plasticity.